The overall goal of this Program is to develop nucleic acid therapeutics based on a mechanistic understanding of how these molecules modulate gene expression in vitro, and in vivo. The program consists of 4 projects and 2 Cores. Each project will investigate in a critical manner different approaches to, and aspects of, modulating gene expression in mammalian cells. The individual projects, and their Investigators are as follows: Kazuko Nishikura (Wistar Institute)- RNAi mediated squelching of Gene Expression in Mammalian Cells; Stephen Liebhaber (University of Pennsylvania)- RNA Decoys- aCP as a Model for Modulating Gene Expression in Erythroid Cells; Eric Pierce (University of Pennsylvania) and Kyong Yoon (Thomas Jefferson University, Philadelphia, PA)- Mechanisms of Gene Repair and Targeting in Embryonic Stem Cells; and Alan M. Gewirtz (University of Pennsylvania)- Developing Nucleic Acid Therapeutics. The projects are supported by the following Cores: Nucleic Acid Synthesis- Ponzy Lu (University of Pennsylvania)-Director; Administration- A. Gewirtz, Director. Each of the project directors is an established investigator with a substantial interest in the biology of gene expression at the transcriptional and translational levels. Each Project Leader brings to the effort a different expertise, which is non-overlapping and highly complementary. Accordingly, the groups' interactions will be highly synergistic and result in a program, which is truly greater than the sum of its parts. All of the investigators are ultimately interested in translating their laboratory findings into the development of more reliable, and more efficient, molecules for silencing gene expression. It is our belief that such molecules will have an important impact on the diagnosis, and treatment of neoplastic diseases.